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Inflammatory bowel disease and oral health ©SEBASTIAN KAULITZKI/Science Library/Getty©SEBASTIAN Photo

J. S. Chandan1 and T. Thomas1 summarise the treatments for inflammatory bowel disease (IBD) and how anti-inflammatory can have side effects that affect the oral cavity.

Inflammatory bowel disease (IBD) mainly comprises of two Risk factors involved in IBD separate inflammatory conditions: Crohn’s disease (CD) and IBD is thought to result from inappropriate and ongoing activation ulcerative colitis (UC). The aetiology of these conditions is of the mucosal facilitated by defects in both the still being explored with current evidence pointing towards intestinal and mucosal immune system.5 There are both a combination of environmental and genetic components. genetic and environmental factors implicated in the aetiology of IBD.6 However, the pathophysiology is understood as a Although traditionally associated with the developed world, recent driven inflammatory response. There is significant association epidemiological studies suggest an increasing incidence in rapidly between IBD and dental conditions such as dental caries, other developing countries, especially in South-East Asia.7 In addition, infections and periodontitis. Anti-inflammatory medications the increased risk of IBD in the immigrant populations in the West such as 5 aminosalicylic acid (5ASA), steroids and biological suggests environment has a role in the development of IBD.8 therapies are the treatment of choice for these chronic conditions, dependent on aetiology. Therefore, this article aims Genetic to educate dentists regarding possible implications IBD and its Detailed genetic mapping has identified specific genetic changes treatment can have for clinical practice and future research. on chromosome 16 carried in families which appear linked to CD, however no significant changes have been mapped as of yet Introduction to UC.9,10 Specifically, variants of the NOD2 gene provide the Inflammatory bowel disease (IBD) is an umbrella term strongest association with susceptibility to CD. NOD2 plays a key mainly comprising of two separate medical conditions: role in regulating the gut mucosal barrier involving, specifically, the Crohn’s disease (CD) and ulcerative colitis (UC). They are microbiota, as well as the related response by the innate and adaptive chronic inflammatory conditions affecting the digestive immune system. The IBDchip European Project showed NOD2 has system that can lead to acute flare-ups of the respective been implicated in ileal location colitis with stenosing and penetrating conditions. CD can affect any part of the GI system (most disease behaviour.11 A genome wide association study has also commonly the small bowel, whereas UC only affects the identified a strong link between the IL23R gene and CD.12 The gene in large bowel.1 particular codes for 23 that plays a role in regulating innate The incidence of IBD is beginning to stabilise in immunity within the intestine.13 Europe with about 2.2 million people suffering from the condition.2 In the UK it is estimated at least 115,000 Cigarette people have CD and around 146,000 have a diagnosis of Unusually, cigarette smoking is associated with decreased rates of UC.3 It is a condition that is most commonly diagnosed incidence of UC and has been associated with protective features during childhood or early adolescence.4 to prevent further flare-ups of the condition14-19 such as relapses,20

1Queen Elizabeth Hospital, Birmingham, B15 2TH

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hospitalisations21 and colectomies.22 Also, immune responses. In addition, it can lead symptoms were also present in a greater complications of the condition are reduced in to inappropriate Th1 pathway stimulation proportion within the active phase cohort those who do smoke. This raises the concept due to decreased inhibition of the TLR2 than in the remission cohort (70.6% vs. 52.1%, of encouraging smoking to prevent adverse stimulation.36 Other important factors P = 0.001). Moreover, aphthous ulcers had a events occurring. However, there is a plethora affecting the innate immune system in substantially increased presence within the of evidence that suggests that smoking has IBD include autophagy defects due to gene active phase when compared with remission adverse effects on overall morbidity outcomes. mutations such as in the ATG16L1 gene, (35.3% vs. 4.2%, P <0.001). In particular, it can increase failure in dental which has been implicated in CD. implants,23 increase the risk of oral cancers and The adaptive immune system is the specific Signs/symptoms of oro-facial IBD increase the incidence of dental infections.24 immune response system, consisting of Bcells that manifest with IBD are Guidelines advocate smoking cessation in and Tcells among others. There have been overwhelmingly that of CD. The most common UC patients. On the contrary CD patients theories that there are two distinct adaptive sites involved are the , buccal mucosa who smoke have a more severe disease course immune system pathologies driving CD and and gingiva.43 Orofacial CD can present with and can increase the incidence of CD with UC. It was suggested that the IL12 cytokine aphthous ulcerations, angular , and further complications.18,25-27 In fact, smoking stimulation resulting in Th1 mediated cobblestoning with or without oedema of the cessation can provide a 65% reduction in upregulation and thereby IFNY could be one lips. Figures 1 and 2 demonstrate some of the risk of relapse versus smokers. This is of the main players in CD. Likewise, in the case these oral manifestations of CD. Mucosal tags comparable to the reduction of risk attributed 28 to immunosuppressive therapy. ‘SIGNS AND SYMPTOMS THAT MANIFEST Other environmental risk factors In observational studies, appendectomies WITH INFLAMMATORY BOWEL DISEASE ARE appear to provide a risk reduction in the development of UC.29 Oral contraceptives OVERWHELMINGLY THAT OF CROHN’S DISEASE. statistically significantly increased the risk for developing CD and appeared to increase the risk of UC.30 The other THE MOST COMMON SITES ARE THE LIPS, important environmental factor playing on the development of IBD is diet control. The BUCCAL MUCOSA AND GINGIVA.’ greatest association appears to be between increased sugar intake and developing IBD.31 This is especially important to note of UC, Th2 mediated reaction in the gingiva should also be treated with considering increased sugar intake can lead to was thought to be a key player. However, recent suspicion. The buccal mucosa can also contain the development of dental caries.32,33 Secondly, research has described mixed cytokine profiles , alongside cobblestone features increased sugar content will be a contributing in UC, and therefore, it is clear that further and ooedema. Pyostomatis vegetans is a rare factor to which already has a causal research needs to be performed to investigate condition that could indicate the presence link with .34 the specific roles of Th1 and Th2 in IBD.37 of CD as well as UC. It is characterised by dramatic erythematous thickened mucosa Pathology of IBD Oral presentations of IBD with widespread erosions. Case reports44,45 The pathophysiology behind IBD has been Current literature suggests that up to have indicated that oro-facial fistulae can be under intense research scrutiny for the last 35% of IBD patients will have an extra- another rare outcome of IBD often presenting decade, and much of it is still unknown. intestinal manifestation.38 The oral cavity as a discharging on the face. The However, it is clear that it consists of complex could potentially be affecting up to 5-50% aetiology of these fistulae is unclear as there interplay between genetic influences, of patients. The wide range is due to the appears to be overlap with granulomatous environmental factors, microbial flora and non-specificity of oral symptoms. However, oro-facial disease.46 the host immune system.35 The dysfunction broadly speaking, this population tends to be of the innate and adaptive immune system made up of CD patients, with children being Conditions associated with IBD is at the centre of the inflammatory process. affected more than adults.39 Older children Current research suggests that IBD patients The innate immune system is the immediate and adolescents in particular are vulnerable to are more likely to undergo dental procedures nonspecific response system of the body oral CD manifestations.40 One of the reasons than a healthy cohort.47 In particular, CD with response times ranging from minutes why it is important to be aware of the signs patients were 1.18 times more likely to to hours. It consists of the epithelial cells, and symptoms of CD is due to the hypothesis undergo dental treatment compared to and natural killer Tcells among that oral inflammation may precede intestinal healthy controls (P <0.000). Removable other cells. The pattern recognition receptors manifestation of disease.41 (+65%), front teeth fillings (+52%), (PCR) such as toll-like receptors and NOD- In a tertiary centre case-control study and endodontic treatment (+46%) in like receptors recognising valid pathogen conducted in Portugal, consisting of 113 particular were more prevalent in the CD associated molecular patterns (PAMPs) are patients with previously diagnosed IBD and cohort. Similarly, UC patients were 1.09 times one of the main triggers for this system. 58 healthy controls, there was a significantly more likely to undergo dental treatment However, mutations in underlying genes increased prevalence of oral symptoms when compared to health controls (P <0.005). In such as NOD2, that plays a key role in compared with the control that did not have particular, these patients were 1.33 times immune tolerance, result in inappropriate IBD (54.9% vs. 24.3%, P = 0.011).42 Oral more likely to have fillings in canines and www.nature.com/BDJTeam BDJ Team 22 ©2017 British Dental Associati on. All ri ghts reserved.

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incisors than the healthy controls (P <0.001). The impact of IBD on oral health is thus well described. However, the exact nature of this relationship is unclear. The underlying inflammatory changes in IBD plays a role in poor oral health, however, the link is not causal aside from in the case of specific oral complications of IBD. The associations mainly appear to be linked to the development of dental caries, periodontal disease and other loosely related conditions through other risk factors associated with the development of IBD, such as high sugar intake.

Dental caries/infection There appears to be a significant association with caries and oral ulcers in IBD compared to the normal population.48 A case control study consisting of 110 participants49 identified children with IBD had statistically significantly higher rates of decayed, missing and filled teeth (dmft) (2.95 vs 0.91). Fig. 1 Oral Crohn’s disease: macrocheileitis IBD patients also have increased rates of (a), angular and mucosal tags (b). lactobacilli and streptococcus mutans found Reproduced with permission from Katsanos 50 K H et al. Non-malignant oral manifestations in their oral cavity contributing to caries. in inflammatory bowel diseases,Aliment The reasoning behind why these increased Pharmacol Ther, 2015; 42, John Wiley and Sons rates of caries and infections are not clear, however, proposed arguments include salivary components (increased bacterial the inflammatory process. Indirect factors concentrations), and diet.51,52 can also play a role and this can be due to As discussed above, a risk factor for patients reduced intake and side effects of concurrent developing IBD is the increased sugar intake . Particularly in CD, involvement Fig. 2 (a-b) Oral Crohn’s disease: that can be associated with further infection. of the small bowel can hinder absorption cobblestoning and linear ulcers in the buccal mucosa. Reproduced with permission from of vital nutrients. Iron malabsorption can Katsanos K H et al. Non-malignant oral Periodontal disease occur if the duodenum and upper jejunum manifestations in inflammatory bowel diseases, Aliment Pharmacol Ther, 2015; 42, John Wiley The association between IBD and periodontal is affected, and this can manifest as angular and Sons disease is starting to emerge in recent cheilitis and .58 On a systemic literature.53 Due to the inflammatory nature level, low iron gives rise to the microcytic of both disorders, it is hypothesised that hypochromic anaemia picture. Involvement Newer monoclonal therapies such underlying IBD can trigger a raised basal of the terminal ileum can result in folate and as golimumab, vedolizumab and ustekinumab cytokine response that can induce periodontal B12 deficiencies causing painful glossitis and are now in use in specialised cases within disease. Several case control studies have stomatitis, among others. This manifests as tertiary centres. been conducted to explore this relationship macrocytic anaemia. Other nutrients prone to The corresponding pathway for CD60 (again further. A German study54 identified that deficiencies include magnesium, potassium, as per individual patient needs) is as follows: twice as many patients with IBD, compared vitamin D, selenium and zinc. Malnutrition 1. Thiopurine therapy (Azathioprine or to those without IBD, had clinic attachment of these micronutrients often results in non- 6mercaptopurine) loss >5 mm, however, mean loss was not specific oral . 2. Methotrexate statistically significant. However, since then 3. Biologic therapy consisting of infliximab/ further prospective trials have identified that Medications adalimumab. IBD patients have higher provenances of The therapeutic route to disease remission periodontal disease, deeper pocket depth and in IBD differs slightly between CD and UC. In the case of colonic CD, 5ASA therapies more .55,56 Steroids play an integral role in induction of may also be used with good efficacy. As remission in both conditions. In summary, the medications overlap largely between Malnutrition the NICE-recommended UC pathway59 (as the conditions we will explore the dental Malnutrition is very prevalent within the per individual patient needs) is as follows: associations related to these medications. IBD population. Literature has previously 1. 5-aminosalicylic acid (5ASA) therapy such It should be noted that these medications estimated this number to be almost one in as sulphasalazine or mesalazine have potent anti-inflammatory and four outpatients, and almost nine out of ten 2. Thiopurine therapy (Azathioprine or immunosuppressant actions and therefore inpatients.57 This could be due to direct factors 6mercaptopurine) reduce the body’s ability to fight infection, such as loss of normal resorptive mechanisms 3. Biologic therapy consisting of infliximab/ which is an important consideration in an and higher nutritional requirements due to adalimumab. oral health context.

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5-ASAs Therefore, it is still worth enquiring about Surgical treatment and biopsy 5-ASAs such as sulphasalazine and mesalazine opportunistic dental screenings whether or Surgical modalities for treatment of oral act as anti-inflammatory medications not these patients have experienced systemic manifestations of IBD are used in cases providing topical relief inside the intestines. symptoms of TB as it is of public health where complications have developed such They do this by reducing synthesis of importance. In addition, as these medications as fistulations and abscesses. In these cases, inflammatory and have been used are still relatively new, the long-term risks of a combination of maxillofacial surgery and for many years.61 They are medications that can them are unknown. Any cause for concern in plastic surgery may be indicated. Orofacial cause a host of side effects from common ones a patient on biologic treatment should ideally surgery is relatively more complex in the including nausea, vomiting and GI upset.62 be escalated to the medical team for thorough IBD cohort. There is evidence to suggest that However, three are of particular importance investigation. this cohort is at higher risk of oropharyngeal and interest to dentists. The first being the perforation.80 Post-operative recovery may risk of drug induced agranulocytosis.63 Treatment of oral lesions also be impaired in these patients due to Agranulocytosis is an acute condition leading The main underlying principle in treating oral concomitant use of systemic steroids and to a severe leucopenia where there a reduction lesions in IBD lies in identifying the cause of potent immunosuppressants. in white blood cells affect the way the body oral lesions. These could be directly due to can fight infection. Secondly, of interest to the IBD, malnutrition or concurrent medication Diet dental profession, 5-ASAs have supposedly use (as mentioned below). Diet is an important factor that can be caused a few cases of which is a Oral involvement of IBD revolves around overlooked in managing oral health swelling of the parotid gland similar to treating the intestinal manifestation of the manifestations of IBD. An early study81 but it is unclear whether this was due to the disease. However, topical and systemic identified that strict elimination diets, where a medication or progression of the condition, medical treatment modalities are available. potential trigger in the diet leading to the flare however, it is still noted as a side effect for the Corticosteroid injections can be applied of aphthous ulcer is identified and removed, medication.64 Thirdly, a few patients have noted locally to the . In addition, symptomatic provide symptomatic relief. The management taste disturbances which may present to the relief is available via use of lidocaine 2% in of diet-related oral manifestations largely dentist before the doctor.65 the most severe cases. Less potent treatment represents replacing the vitamin or mineral modalities take the form of ointments. that is depleted. There are known associations Purine analogues Evidence shows that topical tacrolimus at between decreased ferritin levels and oral Azathioprine and 6mercaptopurine are both relatively low concentrations of 0.5 mg/kg ulcers, therefore, appropriate replacement purine analogues and widely used immune- can be potent in oral manifestations of CD.76 would help prevent development.82 suppressants to dampen the immune response in both conditions.66 Similarly to 5ASAs, these medications can cause an acute leucopenia ‘A STUDY IDENTIFIED THAT STRICT ELIMINATION which can severely impair the body’s effect on fighting infection.67 Secondly, there is a DIETS, WHERE A POTENTIAL TRIGGER IN THE DIET fourfold documented increase in the risk of with these medications which can present in the oral cavity.68,69 It should be noted, LEADING TO THE FLARE OF APHTHOUS ULCER IS however, that there is only a very small absolute increase in the risk of lymphoma occurrence. IDENTIFIED AND REMOVED, PROVIDE RELIEF’ Methotrexate The role of methotrexate in IBD management is rare. However, methotrexate can be Other ointment options include the use of Take home message used as an effective immune-modulator in 1% hydrocortisone three times daily. Steroid From the literature and clinical experience inflammatory bowel disease.70 Of importance (dexamethasone elixir) are earlier, there is an evident association between to dentists, methotrexate can commonly cause also available for symptomatic relief. These IBD and various dental health conditions. ulcerative stomatitis71 and recent case reports methods of treatment, particularly topical Implications for education, practice and have identified Epstein-Barr associated dexamethasone ointments, are effective future research should be considered. lympho-proliferative disorders occurring in treatments for refractory aphthous ulcers the gingiva of patients taking methotroxate, as well.77 Implications for education causing gingival ulceration.72,73 Typically, systemic medical treatment is Dentists should be aware of the conditions reserved for the most severe of oral cases. that comprise IBD and their links to dental Biologic anti-TNF agents Evidence advocating systemic medical conditions such as dental caries, periodontitis Both infliximab and adalimumab are treatment to combat oral manifestation of and other oral infections. Secondly, dentists relatively new antibody-based drugs against IBD consists largely of low sample size studies. should be aware of the medications such TNF (tumour necrosis factor), which is a However, it has been shown that combination patients take for the conditions, which in their cytokine agent in the body’s immune response, therapy of steroids and azathioprine can own right can induce oral signs. upregulated in inflammatory conditions such potentially be beneficial.78 Staines et al. 200779 as IBD. These medications pose fewer adverse suggested that anti-TNF inhibitors can be of Implications for practice effects related to the oral region, however, they benefit in complex oral manifestations such as Dentists should be able to identify oral are associated with reactivation of latent TB.74,75 fistulating oral disease. presentations associated with IBD. Where early www.nature.com/BDJTeam BDJ Team 24 ©2017 British Dental Associati on. All ri ghts reserved.

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